2-177738558-T-C

Variant names:

• chr2-177738558-T-C
• rs1866212
• NM_016953.4:c.1789-10386A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016953.4(PDE11A):​c.1789-10386A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 152,052 control chromosomes in the GnomAD database, including 38,214 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.69 (38214 hom., cov: 31)
• Consequence: PDE11A NM_016953.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 2 publications found

Genes affected

PDE11A (HGNC:8773): (phosphodiesterase 11A) The 3',5'-cyclic nucleotides cAMP and cGMP function as second messengers in a wide variety of signal transduction pathways. 3',5'-cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP to the corresponding 5'-monophosphates and provide a mechanism to downregulate cAMP and cGMP signaling. This gene encodes a member of the PDE protein superfamily. Mutations in this gene are a cause of Cushing disease and adrenocortical hyperplasia. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PDE11A Gene-Disease associations (from GenCC):

• pigmented nodular adrenocortical disease, primary, 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine
• primary pigmented nodular adrenocortical disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016953.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE11A	NM_016953.4	MANE Select	c.1789-10386A>G		intron	N/A	NP_058649.3
	PDE11A	NM_001077197.2		c.1039-10386A>G		intron	N/A	NP_001070665.1
	PDE11A	NM_001077358.2		c.715-10386A>G		intron	N/A	NP_001070826.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE11A	ENST00000286063.11	TSL:1 MANE Select	c.1789-10386A>G		intron	N/A	ENSP00000286063.5
	PDE11A	ENST00000358450.8	TSL:1	c.1039-10386A>G		intron	N/A	ENSP00000351232.4
	PDE11A	ENST00000409504.5	TSL:1	c.715-10386A>G		intron	N/A	ENSP00000386539.1

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104420 AN: 151934 Hom.: 38197 Cov.: 31

Gnomad AFR AF: 0.410

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.821

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.741

Gnomad FIN AF: 0.797

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.795

Gnomad OTH AF: 0.694

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.687 AC: 104477 AN: 152052 Hom.: 38214 Cov.: 31 AF XY: 0.692 AC XY: 51408 AN XY: 74328

African (AFR) AF: 0.410 AC: 16998 AN: 41454

American (AMR) AF: 0.770 AC: 11777 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.821 AC: 2849 AN: 3472

East Asian (EAS) AF: 0.859 AC: 4435 AN: 5164

South Asian (SAS) AF: 0.739 AC: 3549 AN: 4800

European-Finnish (FIN) AF: 0.797 AC: 8430 AN: 10574

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.795 AC: 54075 AN: 67988

Other (OTH) AF: 0.696 AC: 1467 AN: 2108

Alfa AF: 0.704 Hom.: 4929

Bravo AF: 0.678

Asia WGS AF: 0.785 AC: 2727 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.48
DANN	Benign	0.34
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1866212; hg19: chr2-178603286;